We assessed the risk of clinically significant drug interactions in patients receiving antiretrovirals, and their recognition by physicians. Clinically significant drug interactions were recorded in 27% of 159 patients, with 15% of interactions potentially lowering antiretroviral concentrations. Risk of clinically significant drug interactions was significantly related to receipt of protease inhibitors. Only 36% of clinically significant drug interactions were correctly identified by physicians.

Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P ‫؍‬ 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.The failure to achieve and maintain suppression of human immunodeficiency virus (HIV) replication is emerging as a major problem in antiretroviral therapy (ART). One large cohort study has recently reported a mean time before virological failure on first-ART-regimen drugs of 12 months but with markedly decreasing durability for each successive regimen (F. Palella, J. Chmiel, M. Deloria-Knoll, A. Moorman, S. Holmberg, and the HIV Outpatient Investigators, 8th Conf. Retrovir. Opportunistic Infect., abstr. 268B, 2001). Treatment failure is multifactorial and includes viral resistance, poor adherence, and pharmacological and host factors. Much interest has been generated by potential pharmacological mechanisms of failure. HIV replicates within cells; therefore, drugs must penetrate intracellularly at concentrations sufficient to inhibit viral replication. Failure to do so results in the establishment of a sanctuary site where virus may evolve in the absence of selection pressure from the drug (22) or where subtherapeutic levels generate drug-resistant virus with subsequent "seeding" into plasma. Virus from sanctuary sites, such as the central nervous system and seminal fluid, can exhibit genotypic resistance profiles, which differ from peripheral blood isolates (6, 21). Pharmacological studies that examine the cellular and tissue penetration of HIV drugs are crucial to the understanding of sanctuary sites and the subsequent evolution of drug resistance and the failure of ART. This understanding may inform the design of strategies to maximize drug potency. In particular, the roles of cellular efflux transporters such as the P-glycoprotein (P-gp) in limiting the intracellular penetration of drugs and the potential for ritonavir (RTV) to boost intracellular drug accumulation within sanctuary sites deserve further investigation.We have previou...

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